The present invention is related to novel compounds having affinity to one or more GABAB receptors, as well as to their pharmaceutically acceptable salts, solvates and stereoisomers. The invention is also related to processes for their preparation, pharmaceutical compositions containing said therapeutically active compounds and to the use of said active compounds in therapy.
Reflux
Gastro-oesophageal reflux disease (GORD) is the most prevalent upper gastrointestinal tract disease. Current therapy has aimed at reducing gastric acid secretion, or at reducing oesophageal acid exposure by enhancing oesophageal clearance, lower oesophageal sphincter tone and gastric emptying. The major mechanism behind reflux has earlier been considered to depend on a hypotonic lower oesophageal sphincter. However recent research (e.g. Holloway and Dent (1990) Gastroenterol. Clin. N. Amer. 19, 517-535) has shown that most reflux episodes occur during transient lower oesophageal sphincter relaxations, hereinafter referred to as TLOSR, i.e. relaxations not triggered by swallows. It has also been shown that gastric acid secretion usually is normal in patients with GORD.
Consequently, there is a need for compounds which reduce the incidence of TLOSR and thereby prevent reflux.
A pharmaceutical composition comprising a local anaesthetic, adapted to inhibit relaxation of the lower oesophageal sphicter is disclosed in WO 87/04077 and in U.S. Pat. No. 5,036,057. Recently GABAB-receptor agonists have been shown to inhibit TLOSR, as disclosed in WO 98/11885.
GABAB Receptor Agonists
GABA (4-aminobutanoic acid) is an endogenous neurotransmitter in the central and peripheral nervous systems. Receptors for GABA have traditionally been divided into GABAA and GABAB receptor subtypes. GABAB receptors belong to the superfamily of G-protein coupled receptors. GABAB receptor agonists are being described as being of use in the treatment of CNS disorders, such as muscle relaxation in spinal spasticity, cardiovascular disorders, asthma, gut motility disorders such as irritable bowel syndrome (IBS) and as prokinetic and anti-tussive agents. GABAB receptor agonists have also been disclosed as useful in the treatment of emesis (WO 96/11680) and recently, as mentioned above, in the inhibition of TLOSR (WO 98/11885).
The most studied GABAB receptor agonist is baclofen (4-amino-3-(chlorophenyl)butanoic acid) disclosed in the Swiss patent No. CH 449,046. Baclofen has for several years been used as an antispastic agent. EP 0356128 describes the use of the specific compound (3-aminopropyl)methylphosphinic acid, as a potent GABAB receptor agonist, in therapy. EP 0181833 discloses substituted 3-aminopropylphosphinic acids which are found to have very high affinities towards GABAB receptor sites. In analogy to baclofen, the compounds can be used as for instance muscle relaxants. EP 0399949 discloses derivatives of (3-aminopropyl)methylphosphinic acid which are described as potent GABAB receptor agonists. These compounds are stated to be useful as muscle relaxants. EP 0463969 and FR 2722192 are both applications related to 4-aminobutanoic acid derivatives having different heterocyclic substituents at the 3-carbon of the butyl chain. Structure-activity relationships of several phosphinic acid analogues with respect to their affinities to the GABAB receptor as well as their muscle relaxant effect are discussed in J. Med. Chem. (1995), 38, 3297-3312. The conclusion in said article is that considerably stronger muscle relaxation could be achieved with the (S)-enantiomer of 3-amino-2-hydroxy-propylmethylphosphinic acid than with baclofen and without the occurrence of unwanted CNS effects.
The present invention provides novel compounds of the formula I 
wherein
R1 represents hydrogen, hydroxy, lower alkyl, lower alkoxy or halogen;
R2 represents hydroxy, mercapto, halogen or an oxo group;
R3 represents hydrogen or lower alkyl (optionally substituted with hydroxy, mercapto, lower alkoxy, aryl or lower thioalkoxy);
R4 represents hydrogen, lower alkyl (optionally substituted with aryl) or aryl;
R5 represents methyl, fluoromethyl, difluoromethyl or trifluorormethyl;
and pharmaceutically acceptable salts, solvates and the stereoisomers thereof, with the exceptions of:
i) the racemate of (3-amino-2-hydroxypropyl)methylphosphinic acid,
ii) (S)-(3-amino-2-hydroxypropyl)methylphosphinic acid,
iii) (R)-(3-amino-2-hydroxypropyl)methylphosphinic acid,
iv) (3-amino-2-hydroxypropyl)difluoromethylphosphinic acid, and
v) (3-amino-2-oxopropyl)methylphosphinic acid.
Preferrably the compound is one of (3-amino-2-fluoropropyl)(methyl)phosphinic acid, (2R)-(3-amino-2-fluoropropyl)(methyl)phosphinic acid, (2S)-(3-amino-2-fluoropropyl)(methyl)phosphinic acid, (3-amino-2-fluoro-1-methylpropyl)(methyl)phosphinic acid or pharmaceutically acceptable salts, solvates or the stereoisomers thereof.
Within the scope of the invention, it is to be understood that when R2 is an oxo group the bond between R2 and the carbon is a double bond.
Furthermore, within the scope of the invention, it is to be understood by xe2x80x9clowerxe2x80x9d radicals and compounds, for example, those having up to and including 7, especially up to and including 4, carbon atoms. Also the general terms have the following meanings:
Lower alkyl is, for example, C1-C4 alkyl, such as methyl, ethyl, n-propyl or n-butyl, also isopropyl, isobutyl, secondary butyl or tertiary butyl, but may also be a C5-C7 alkyl group such as a pentyl, hexyl or heptyl group.
Lower alkoxy is, for example, C1-C4 alkoxy, such as methoxy, ethoxy, n-propoxy or n-butoxy, also isopropoxy, isobutoxy, secondary butoxy or tertiary butoxy, but may also be a C5-C7 alkoxy group, such as a pentoxy, hexoxy or heptoxy group.
Lower thioalkoxy is, for example, C1-C4 thioalkoxy, such as thiomethoxy, thioethoxy, n-thiopropoxy or n-thiobutoxy, also thioisopropoxy, thioisobutoxy, secondary thiobutoxy or tertiary thiobutoxy, but may also be a C5-C7 thioalkoxy group, such as a thiopentoxy, thiohexoxy or thioheptoxy group.
Halogen is halogen of an atomic number up to and including 35, such as flourine or chlorine, and less prefered bromine.
The compounds according to formula I of the invention are of amphoteric nature and may be presented in the form of internal salts. They can also form acid addition salts and salts with bases. Such salts are particularly pharmaceutically acceptable acid addition salts, as well as pharmaceutically acceptable salts formed with bases. Suitable acids for the formation of such salts include, for example, mineral acids such as hydrochloric, hydrobromic, sulfuric, or phosphoric acid or organic acids such as sulfonic acids and carboxylic acids. Salts with bases are, for example, alkali metal salts, e.g. sodium or potassium salts, or alkaline earth metal salts, e.g. calcium or magnesium salts as well as ammonium salts, such as those with ammonia or organic amines. The salts may be prepared by conventional methods.
When one or more stereocentre is present in the molecule, the compounds according to formula I can be in the form of a stereoisomeric mixture, i.e. a mixture of diastereomers and/or racemates, or in the form of the single stereoisomers, i.e. the single enantiomer and/or diastereomer. The present compounds can also be in the form of solvates, e.g. hydrates.
All of the compounds according to the formula I can be used for the inhibition of TLOSR, and thus for the treatment of gastro-oesophageal reflux disease. The said inhibition of TLOSR also implies that all of the compounds of formula I can be used for the treatment of regurgitation in infants. Effective management of regurgitation in infants would be an important way of managing failure to thrive due to excessive loss of ingested nutrient. Furthermore the novel compounds can be used for the treatment of GORD- or non-GORD related asthma, belching, coughing, pain, cocaine addiction, hiccups, IBS, dyspepsia, emesis and nociception.
The present invention provides compounds having surprisingly high potencies and/or therapeutic index.
Preparation
The compounds according to formula I of the present invention may be prepared by one of the following methods.
A) A compound of formula II 
xe2x80x83in which R1, R3 and R5 are as defined above in formula I, Z is a protecting group such as t-butyloxycarbonyl and Y is hydrogen or a protecting group such as lower alkyl, which compound of formula II may have been synthesized by a condensation reaction according to Scheme 1 employing an appropriate N-protected amino acid ester in which R3 is as defined above in formula I, W is a protecting group such as lower alkyl and Z is as defined in formula II, and a suitable protected phosphinic acid derivative in which R1 and R5 is as defined above in formula I, Y is as defined in formula II, and a base such as lithium diisopropylamide, 
a) converted optionally by an N-alkylation reaction in order to introduce R4 if R4 is desired to be not equal to hydrogen, and thereafter a hydrolytic reaction to obtain a compound of formula III 
xe2x80x83wherein R1, R3, R4 and R5 are as defined above in formula I, and optionally convert the above resulting compound III into another chemical compound of the formula III and/or sepatate a resulting mixture of isomers into the individual isomers and/or convert a resulting salt into the free compound of the formula III and/or into another salt and/or convert a resulting free compound of the formula III into a salt to correspond to the above definition, or
b) converted by a reductive reaction, optionally an N-alkylation reaction if R4 is desired to be not equal to hydrogen, and finally a hydrolytic reaction to a compound of formula IV 
xe2x80x83wherein R1, R3, R4 and R5 are as defined above in formula I, and optionally convert the above resulting compound IV into another chemical compound of the formula IV and/or sepatate a resulting mixture of isomers into the individual isomers and/or convert a resulting salt into the free compound of the formula IV and/or into another salt and/or convert a resulting free compound of the formula IV into a salt to correspond to the above definition, or
c) converted by a reductive reaction followed by a deoxohalogenation reaction, optionally an N-alkylation reaction in order to introduce R4 if R4 is desired to be not equal to hydrogen, and finally a hydrolytic reaction to obtain a compound of formula VI 
xe2x80x83wherein R1, R3 and R4 are as defined above in formula I and Halo is a halogen atom, and optionally convert the above resulting compound VI into another chemical compound of the formula VI and/or sepatate a resulting mixture of isomers into the individual isomers and/or convert a resulting salt into the free compound of the formula VI and/or into another salt and/or convert a resulting free compound of the formula VI into a salt to correspond to the above definition;
or B) a compound of formula VII 
xe2x80x83in which R1, R3 and R5 are as defined above in formula I, U is a group that can be converted to a xe2x80x94NH2 group, and Y is hydrogen or a protecting group such as lower alkyl, which compound VII may have been synthesized by a condensation reaction according to Scheme 2 employing an 2,3-epoxypropyl derivative, such as an appropriate N-protected 2,3-epoxypropylamine derivative or an epichlorohydrin derivative, in which R1 and R3 is as defined above in formula I, and a suitable protected phosphinic acid derivative activated by O-silylation, in which R5 and Y are as defined in formula VII, and a Lewis acid such as anhydrous ZnCl2, 
xe2x80x83is
a) converted by a reaction where the trimethylsilyl group is replaced by a hydrogen atom, a reaction where the U group as defined in formula VII is converted to xe2x80x94NHR4 wherein R4 is as defined above in formula I, and finally a hydrolytic reaction to obtain a compound of formula IV 
xe2x80x83wherein R1, R3, R4 and R5 are as defined above in formula I, and optionally convert the above resulting compound IV into another chemical compound of the formula IV and/or sepatate a resulting mixture of isomers into the individual isomers and/or convert a resulting salt into the free compound of the formula IV and/or into another salt and/or convert a resulting free compound of the formula IV into a salt to correspond to the above definition, or
b) converted by a reaction where the trimethylsilyl group is replaced by hydrogen, an oxidative reaction, a reaction where the U group as defined in formula VII is converted to xe2x80x94NHR4 wherein R4 is as defined above in formula I, and finally a hydrolytic reaction to obtain a compound of formula III 
xe2x80x83wherein R1, R3, R4 and R5 are as defined above in formula I, and optionally convert the above resulting compound III into another chemical compound of the formula III and/or sepatate a resulting mixture of isomers into the individual isomers and/or convert a resulting salt into the free compound of the formula III and/or into another salt and/or convert a resulting free compound of the formula III into a salt to correspond to the above definition, or
c) converted by a reaction where the trimethylsilyl group is replaced by hydrogen, a deoxohalogenation reaction, a reaction where the U group as defined in formula VII is converted to xe2x80x94NHR4 wherein R4 is as defined above in formula I, and finally a hydrolytic reaction to obtain a compound of formula VI 
xe2x80x83wherein R1, R3, R4 and R5 are as defined above in formula I, and Halo is a halogen atom, and optionally convert the above resulting compound VI into another chemical compound of the formula VI and/or sepatate a resulting mixture of isomers into the individual isomers and/or convert a resulting salt into the free compound of the formula VI and/or into another salt and/or convert a resulting free compound of the formula VI into a salt to correspond to the above definition;
or C) a compound of formula VIII 
xe2x80x83in which R1 and R5 are as defined above in formula I, Q is an electron-withdrawing group, such as for instance xe2x80x94CN or xe2x80x94CO2Et which can be converted to a xe2x80x94CH2NH2 group, and Y is hydrogen or a protecting group such as lower alkyl, and Halo is a halogen atom, which compound of formula VIII may have been synthesized by an addition reaction according to Scheme 3 employing an unsaturated compound in which R1 is as defined above in formula I, Q and Halo are as defined in formula VIII, and a suitable protected phosphinic acid derivative activated by O-silylation, in which R5 and Y are as defined in formula VIII, 
xe2x80x83is converted by a reaction where the Q group is being converted to xe2x80x94NHR4 wherein R4 is as defined above in formula I, and a hydrolytic reaction to obtain a compound of formula IX 
xe2x80x83wherein R1 and R4 are as defined above in formula I and Halo is a halogen atom, and optionally convert the above resulting compound IX into another chemical compound of the formula IX and/or sepatate a resulting mixture of isomers into the individual isomers and/or convert a resulting salt into the free compound of the formula IX and/or into another salt and/or convert a resulting free compound of the formula IX into a salt to correspond to the above definition;
or D) a compound of formula X, optionally as an individual stereo isomer, 
xe2x80x83in which R1, R3, R4 and R5 are as defined in formula I, Z is a protecting group such as t-butyloxycarbonyl and Halo is a halogen atom, which compound of formula X may have been synthesized by a substitution reaction according to Scheme 4 employing an electrophilic compound in which R1, R3 and R4 are as defined above, L is a leaving group such as iodo, Z and Halo are as defined above, and an activated by O-silylation methyl phosphinic acid derivative in which R5 is as defined above, 
xe2x80x83is converted by a hydrolytic reaction to a compound of formula VI 
xe2x80x83wherein R1, R3, R4 and R5 are as defined above in formula I, and optionally convert the above resulting compound VI into another chemical compound of the formula VI and/or sepatate a resulting mixture of isomers into the individual isomers and/or convert a resulting salt into the free compound of the formula VI and/or into another salt and/or convert a resulting free compound of the formula VI into a salt to correspond to the above definition;
or E) a compound of formula XI, optionally as an individual stereo isomer, 
xe2x80x83in which R1, R3 and R4 are as defined in formula I, Z is a protecting group such as t-butyloxycarbonyl and Halo is a halogen atom, which compound of formula XI may have been synthesized by a substitution reaction according to Scheme 5 employing an electrophilic compound in which R1, R3 and R4 are as defined above, L is a leaving group such as iodo, Z and Halo are as defined above, and phosphinic acid activated by O-silylation, 
xe2x80x83is converted by a hydrolytic reaction and then a P-alkylation reaction to a compound of formula VI 
xe2x80x83wherein R1, R3, R4 and R5 are as defined above in formula I, and optionally convert the above resulting compound VI into another chemical compound of the formula VI and/or sepatate a resulting mixture of isomers into the individual isomers and/or convert a resulting salt into the free compound of the formula VI and/or into another salt and/or convert a resulting free compound of the formula VI into a salt to correspond to the above definition;
or F) a compound of formula XII 
xe2x80x83in which R1, R3, R4 and R5 are as defined above in formula I, and Y is hydrogen or a protecting group such as lower alkyl, which compound of formula XII may have been synthesized by an addition reaction according to Scheme 6 treating an unsaturated phosphinic acid derivative, in which R1, R3, R4 and R5 are as defined above in formula I, with H2S, a mercaptide ion (HSxe2x88x92) or a protected mercapto compound such as benzyl thiol in which case the protective group thereafter is removed 
xe2x80x83is converted by a hydrolytic reaction to a compound of formula XIII, 
xe2x80x83in which R1, R3, R4 and R5 are as defined above in formula I, and optionally convert the above resulting compound XIII into another chemical compound of the formula XIII and/or sepatate a resulting mixture of isomers into the individual isomers and/or convert a is resulting salt into the free compound of the formula XIII and/or into another salt and/or convert a resulting free compound of the formula XIII into a salt to correspond to the above definition;
The invention will now be described more in detail by the following examples which are not to be construed as limiting the invention.